Generalized pustular conditions of the skin include pustular psoriasis, Reiter's disease and subcorneal pustular dermatosis. Medications can cause generalized pustular eruptions (i.e. exanthematous pustulosis) or more localized reactions (i.e. acneiform drug eruptions) which usually involve the face, chest and back. Localized pustular eruptions are seen on the hands and feet in adults with pustulosis palmaris et plantaris and acrodermatitis continua; on the face in patients with acne vulgaris, rosacea, and perioral dermatitis; and on the trunk and/or extremities in patients with folliculitis. A separate condition known as eosinophilic folliculitis occurs in individuals with advanced human immunodeficiency disease.
Acne vulgaris (acne) is a multifactorial inflammatory skin condition caused by changes in the pilosebaceous units, which are skin structures consisting of a large, multilobed sebaceous gland, a rudimentary hair and a wide follicular canal lined with stratified squamous epithelium. The pilosebaceous units are found over most of the body surface but are largest and most numerous on the face, chest and upper back. Acne is the most common pustular condition of the skin, disfiguring people with inflammatory and non-inflammatory lesions (including pustules, papules and comedones) during the active phase, and with atrophic scars afterwards. The condition is most common in puberty and in most instances diminishes over time, disappearing or at least decreasing after the person reaches the early twenties. However, some individuals continue to suffer from acne throughout adulthood.
The basic lesion of acne is the microcomedo which forms from an accumulation of sebum, the sebaceous gland secretion, and keratinous debris from skin cells and results in a visible closed comedo or whitehead. Its continued distension causes an open comedo, or blackhead, which gets its dark color from oxidized melanin. Blackheads and microcysts are noninflammatory lesions of acne, but some comedones evolve into inflammatory papules, pustules, or nodules, and can become chronic granulomatous lesions. When inflammation develops, neutrophil infiltration occurs. These neutrophils secrete hydrolytic enzymes that cause further damage. In pustules, neutrophils are present much earlier. More persistent lesions exhibit granulomatous histology that can lead to scarring.
The main goals when treating acne are to minimize the number and severity of lesions, prevent scarring, limit disease duration, and reduce the social and psychological stress that affects many patients, particularly teenagers. Conventional treatment is directed at correcting the three major factors that seem to cause acne: (1) androgenic stimulation of the sebaceous glands and increased sebum production; (2) abnormal keratinization and impaction in the pilosebaceous canal causing obstruction of sebum flow; and (3) proliferation of P. acnes, the bacteria that infects acne lesions. Thus, topical agents that remove comedones (i.e. topical retinoids) are particularly effective because they normalize desquamination within the follicular orifice, which allows the sebum to flow freely onto the surface of the skin. Retinoids such as dalpalene, tretinoin, and tazarotene have been shown to have efficacy in treating mild to moderate acne, but all three are reported to have skin-irritating side effects including erythema, pruritis, burning/stinging and scaling/flaking (Physicians' Desk Reference®, 56th ed. 2002, p. 2523, hereinafter referred to as “PDR”). In fact, the side effects of retinoid use are so extreme that many individuals cannot tolerate topical application of these agents at all.
There are many products on the market to treat acne. Unfortunately, many of them have no scientifically proven effects. Those few products which are useful typically show little improvement in the first week or two of use, after which the acne decreases over approximately 3 months, then improvement levels off. Short courses of cortisone, antibiotics and many laser therapies offer a quick reduction in the redness, swelling and inflammation when used correctly, but none of these empty the pore of all the materials that trigger the inflammation.
Treatment regimens often involve exfoliation to reduce or prevent shedding of dead skin cells into the pore and causing its blockage. This can be done either mechanically using an abrasive cloth or a liquid scrub, or chemically. Common chemical exfoliating agents include salicylic acid and glycolic acid, which encourage the destruction of the top layer of skin cells to prevent a build-up of dead cells which combine with sebum to block pores. Chemical exfoliation also helps to unblock already clogged pores. Depending on the type of exfoliation used, some visible flaking of the skin is possible. Moisturizers and anti-acne topical treatments containing chemical exfoliating agents are available over-the-counter. However, mechanical exfoliation is less commonly used as many benefits derived from the exfoliation are negated by the act of mechanically rubbing and irritating the skin.
In addition, over-the-counter topical bactericidal products containing benzoyl peroxide are common used. Benzoyl peroxide kills P. acnes, which may help prevent formation of new lesions, and acts as a keratolytic (a chemical that dissolves the keratin plugging the pores). Unlike antibiotics, benzoyl peroxide has the advantage of being a strong oxidizer and thus does not appear to generate bacterial resistance. However, it routinely causes dryness, local irritation and redness so it should be combined with suitable moisturizers. Antibiotics such as tetracycline are also useful, as are anti-inflammatory agents such as topical steroids.
Phototherapy using intense blue light generated by fluorescent lighting, dichroic bulbs, LEDs or lasers are also useful treatments. Used twice weekly, phototherapy has been shown to reduce the number of acne lesions significantly and is even more effective when applied daily. The mechanism appears to be that a porphyrin (Coproporphyrin III) produced within P. acnes generates free radicals when irradiated by blue light. These free radicals ultimately kill the bacteria. Since porphyrins are not otherwise present in skin, and no UV light is employed, it appears to be safe and has been approved by the FDA. Unlike most of the other treatments, few if any negative side effects are typically experienced, and the development of bacterial resistance to the treatment seems very unlikely.
Other less common treatments include Azelaic acid (brand names Azelex, Finevin, Skinoren); orally administered zinc gluconate; sulfur as a topical treatment in soaps, creams, shampoos, etc., due to its antibacterial and antifungal properties; Tea Tree Oil (Melaleuca Oil), which has been shown to be an effective anti-inflammatory in skin infections; heat therapy at a specific temperature to kill the P. acnes bacteria; nicotinamide (Vitamin B3) used topically in the form of a gel, which seems to have anti-inflammatory properties; and laser surgery, which has been in use for some time to reduce the scars left behind by acne, for prevention of acne formation itself.
In summary, currently available treatments have exhibited limited success, most have side effects and some are costly. There is no cure for acne on the market today. Therefore, it is an object of the instant invention to provide treatments and a cure for this unmet medical need as well as treatments for other pustular conditions of the skin.